Melanoma is one of the fastest growing cancer incidences in the world. Disease detected early can be cured by surgery, but metastatic melanoma is lethal. Recent blockbusters extend life, but response is low; resistance develops almost invariably (5 y survival 17%); and side effects can be severe. Our Phase I R&D demonstrated the feasibility of our systemic targeted radionuclide therapy for metastatic melanoma. In this Phase II project, innovations to systemic-targeted radionuclide therapy for melanoma developed in Phase I are optimized. Achieving three Objectives will provide data needed to design pharmcology/toxicology studies and an IND application to the FDA for human trials.